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1.
Mutat Res ; 863-864: 503313, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33678245

RESUMO

Biological dosimetry of ionizing radiation (IR) exposure relies on validated cytogenetic tests measuring the frequencies of micronuclei (MN) and dicentric chromosomes (DC). IR also causes oxidative damage of biomolecules, including DNA. We evaluated IR-induced genotoxic and oxidative damage in a carefully defined cohort of healthy donors, reducing confounding factors as much as possible. Frequencies of MN and DC (peripheral blood lymphocyte cultures) and oxidative stress parameters (plasma) were quantified. We observed dose dependence of both cytogenetic and biochemical endpoints, independent of age, sex, and smoking habits. Oxidative stress parameters, especially oxidative stress index, malondialdehyde, advanced oxidation protein products, and catalase, may be used confidently to assess IR-induced damage, if cytogenetic results are unavailable.


Assuntos
Aberrações Cromossômicas/efeitos da radiação , Linfócitos/metabolismo , Estresse Oxidativo/efeitos da radiação , Plasma/metabolismo , Lesões por Radiação/metabolismo , Radiação Ionizante , Adulto , Feminino , Humanos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Lesões por Radiação/patologia
2.
J Cancer Res Clin Oncol ; 147(4): 987-1006, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33547489

RESUMO

BACKGROUND: Greater than half of cancer patients experience radiation therapy, for both radical and palliative objectives. It is well known that researches on radiation response mechanisms are conducive to improve the efficacy of cancer radiotherapy. p21 was initially identified as a widespread inhibitor of cyclin-dependent kinases, transcriptionally modulated by p53 and a marker of cellular senescence. It was once considered that p21 acts as a tumour suppressor mainly to restrain cell cycle progression, thereby resulting in growth suppression. With the deepening researches on p21, p21 has been found to regulate radiation responses via participating in multiple cellular processes, including cell cycle arrest, apoptosis, DNA repair, senescence and autophagy. Hence, a comprehensive summary of the p21's functions in radiation response will provide a new perspective for radiotherapy against cancer. METHODS: We summarize the recent pertinent literature from various electronic databases, including PubMed and analyzed several datasets from Gene Expression Omnibus database. This review discusses how p21 influences the effect of cancer radiotherapy via involving in multiple signaling pathways and expounds the feasibility, barrier and risks of using p21 as a biomarker as well as a therapeutic target of radiotherapy. CONCLUSION: p21's complicated and important functions in cancer radiotherapy make it a promising therapeutic target. Besides, more thorough insights of p21 are needed to make it a safe therapeutic target.


Assuntos
Senescência Celular , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Neoplasias/radioterapia , Radiação Ionizante , Animais , Inibidor de Quinase Dependente de Ciclina p21/genética , Humanos , Neoplasias/genética , Neoplasias/patologia , Transdução de Sinais
3.
Int J Nanomedicine ; 16: 851-865, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574666

RESUMO

Background: Ionizing radiation (IR) is commonly used in triple-negative breast cancer (TNBC) treatment regimens. However, off-target toxicity affecting normal tissue and grueling treatment regimens remain major limitations. Hyperthermia is one of the greatest IR sensitizers, but only if heat is administered simultaneously or immediately prior to ionizing radiation. Difficulty in co-localizing ionizing radiation (IR) in rapid succession with hyperthermia, and confining treatment to the tumor have hindered widespread clinical adoption of combined thermoradiation treatment. Metal nanoparticle-based approaches to IR sensitization and photothermal heat generation may aid in overcoming these issues and improve treatment specificity. Methods: We assessed the potential to selectively treat MDA-MB-231 TNBC cells without affecting non-malignant MCF-10A breast cells using a multimodal approach based upon combined photothermal therapy, IR sensitization, and specific cytotoxicity using triangular silver nanoparticles (TAgNPs) with peak absorbance in the near-infrared light (NIR) spectrum. Results: We found that TAgNP-mediated photothermal therapy and radiosensitization offer a high degree of specificity for treatment of TNBC without affecting non-malignant mammary epithelial cells. Discussion: If given at a high enough dose, IR, heat, or TAgNPs alone could be sufficient for tumor treatment. However, when the dose of one or all of these modalities increases, off-target effects also increase. The challenge lies in identifying the minimal doses of each individual treatment such that when combined they provide maximum selectivity for treatment of TNBC cells with minimum off-target effects on non-malignant breast cells. Our results provide proof of concept that this combination is highly selective for TNBC cells while sparing non-malignant mammary epithelial cells. This treatment would be particularly important for patients undergoing breast conservation therapy and for treatment of invasive tumor margins near the periphery where each individual treatment might be at a sub-therapeutic level.


Assuntos
Nanopartículas Metálicas/uso terapêutico , Radiação Ionizante , Prata/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Carcinogênese/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Terapia Combinada , Feminino , Humanos , Raios Infravermelhos , Nanopartículas Metálicas/ultraestrutura , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Prata/farmacologia , Neoplasias de Mama Triplo Negativas/patologia
4.
Environ Sci Pollut Res Int ; 28(13): 15584-15596, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33533004

RESUMO

Ionizing radiation (IR) is a form of high energy. It poses a serious threat to organisms, but radiotherapy is a key therapeutic strategy for various cancers. It is significant to reduce radiation injury but maximize the effect of radiotherapy. MicroRNAs (miRNAs) are posttranscriptionally regulatory factors involved in cellular radioresponse. In this review, we show how miRNAs regulate important genes on cellular response to IR-induced damage and how miRNAs participate in IR-induced carcinogenesis. Additionally, we summarize the experimental and clinical evidence for miRNA involvement in radiotherapy and discuss their potential for improvement of radiotherapy. Finally, we highlight the role that miRNAs play in accident exposure to IR or radiotherapy as predictive biomarker. miRNA therapeutics have shown great perspective in radiobiology; miRNA may become a novel strategy for damage and protection against IR.


Assuntos
MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , Neoplasias/genética , Neoplasias/radioterapia , Radiação Ionizante
5.
Mutat Res ; 861-862: 503301, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33551102

RESUMO

Ataxia-telangiectasia (AT) is a rare inherited recessive disorder which is caused by a mutated Ataxia-telangiectasia mutated (ATM) gene. Hallmarks include chromosomal instability, cancer predisposition and increased sensitivity to ionizing radiation. The ATM protein plays an important role in signaling of DNA double-strand breaks (DSB), thereby phosphorylating the histone H2A.X. Non-functional ATM protein leads to defects in DNA damage response, unresolved DSBs and genomic instability. The aim of this study was to evaluate chromosomal aberrations and γH2A.X foci as potential radiation sensitivity biomarkers in AT patients. For this purpose, lymphocytes of 8 AT patients and 10 healthy controls were irradiated and induced DNA damage and DNA repair capacity were detected by the accumulation of γH2A.X foci. The results were heterogeneous among AT patients. Evaluation revealed 2 AT patients with similar γH2A.X foci numbers as controls after 1 h while 3 patients showed a lower induction. In regard to DNA repair, 3 of 5 AT patients showed poor damage repair. Therefore, DNA damage induction and DNA repair as detected by H2A.X phosphorylation revealed individual differences, seems to depend on the underlying individual mutation and thus appears not well suited as a biomarker for radiation sensitivity. In addition, chromosomal aberrations were analyzed by mFISH. An increased frequency of spontaneous chromosomal breakage was characteristic for AT cells. After irradiation, significantly increased rates for non-exchange aberrations, translocations, complex aberrations and dicentric chromosomes were observed in AT patients compared to controls. The results of this study suggested, that complex aberrations and dicentric chromosomes might be a reliable biomarker for radiation sensitivity in AT patients, while non-exchange aberrations and translocations identified both, spontaneous and radiation-induced chromosomal instability.


Assuntos
Ataxia Telangiectasia/genética , Aberrações Cromossômicas , Histonas/genética , Tolerância a Radiação , Adolescente , Adulto , Ataxia Telangiectasia/patologia , Ataxia Telangiectasia/radioterapia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Reparo do DNA , Feminino , Humanos , Masculino , Fosforilação , Radiação Ionizante , Adulto Jovem
6.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33498964

RESUMO

Sulfur mustard (SM) is a chemical warfare agent that can damage DNA via alkylation and oxidative stress. Because of its genotoxicity, SM is cancerogenic and the progenitor of many chemotherapeutics. Previously, we developed an SM-resistant cell line via chronic exposure of the popular keratinocyte cell line HaCaT to increasing doses of SM over a period of 40 months. In this study, we compared the genomic landscape of the SM-resistant cell line HaCaT/SM to its sensitive parental line HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array Comparative Genomic Hybridization (array CGH), employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations, and derived mutational signatures by whole-genome sequencing. We observed that chronic SM exposure eliminated the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability toward genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double-strand breaks and their misrepair. HaCaT/SM-specific single-nucleotide variants showed enrichment of C > A and T > A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology, this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.


Assuntos
Aberrações Cromossômicas/induzido quimicamente , Dano ao DNA , Queratinócitos/efeitos dos fármacos , Gás de Mostarda/toxicidade , Mutação , Radiação Ionizante , Alquilantes/farmacologia , Alquilantes/toxicidade , Linhagem Celular , Aberrações Cromossômicas/efeitos da radiação , Hibridização Genômica Comparativa , DNA/efeitos dos fármacos , DNA/metabolismo , DNA/efeitos da radiação , Adutos de DNA , Quebras de DNA de Cadeia Dupla , Humanos , Gás de Mostarda/farmacologia , Estresse Oxidativo
7.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466349

RESUMO

Following exposure to high doses of ionizing radiation, diverse strains of vertebrate species will manifest varying levels of radiation sensitivity. To understand the inter-strain cellular and molecular mechanisms of radiation sensitivity, two mouse strains with varying radiosensitivity (C3H/HeN, and CD2F1), were exposed to total body irradiation (TBI). Since Insulin-like Growth Factor-1 (IGF-1) signaling pathway is associated with radiosensitivity, we investigated the link between systemic or tissue-specific IGF-1 signaling and radiosensitivity. Adult male C3H/HeN and CD2F1 mice were irradiated using gamma photons at Lethal Dose-70/30 (LD70/30), 7.8 and 9.35 Gy doses, respectively. Those mice that survived up to 30 days post-irradiation, were termed the survivors. Mice that were euthanized prior to 30 days post-irradiation due to deteriorated health were termed decedents. The analysis of non-irradiated and irradiated survivor and decedent mice showed that inter-strain radiosensitivity and post-irradiation survival outcomes are associated with activation status of tissue and systemic IGF-1 signaling, nuclear factor erythroid 2-related factor 2 (Nrf2) activation, and the gene expression profile of cardiac mitochondrial energy metabolism pathways. Our findings link radiosensitivity with dysregulation of IGF-1 signaling, and highlight the role of antioxidant gene response and mitochondrial function in radiation sensitivity.


Assuntos
Antioxidantes/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Tolerância a Radiação/fisiologia , Transdução de Sinais/fisiologia , Animais , Relação Dose-Resposta à Radiação , Raios gama , Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Radiação Ionizante , Irradiação Corporal Total/métodos
8.
Int J Mol Sci ; 22(1)2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33401559

RESUMO

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) mediate anti-viral response through mitochondria. In addition, RLR activation induces anti-tumor effects on various cancers. We previously reported that the RLR agonist Poly(I:C)-HMW/LyoVec™ (Poly(I:C)) enhanced radiosensitivity and that cotreatment with Poly(I:C) and ionizing radiation (IR) more than additively increased cell death in lung adenocarcinoma cells, indicating that Poly(I:C) modulates the cellular radiation response. However, it remains unclear how mitochondria are involved in the modulation of this response. Here, we investigated the involvement of mitochondrial dynamics and mitochondrial ribosome protein death-associated protein 3 (DAP3) in the modulation of cellular radiation response by Poly(I:C) in A549 and H1299 human lung adenocarcinoma cell lines. Western blotting revealed that Poly(I:C) decreased the expression of mitochondrial dynamics-related proteins and DAP3. In addition, siRNA experiments showed that DAP3, and not mitochondrial dynamics, is involved in the resistance of lung adenocarcinoma cells to IR-induced cell death. Finally, we revealed that a more-than-additive effect of cotreatment with Poly(I:C) and IR on increasing cell death was diluted by DAP3-knockdown because of an increase in cell death induced by IR alone. Together, our findings suggest that RLR agonist Poly(I:C) modulates the cellular radiation response of lung adenocarcinoma cells by downregulating DAP3 expression.


Assuntos
Adenocarcinoma de Pulmão/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , Poli I-C/farmacologia , Proteínas de Ligação a RNA/metabolismo , Radiação Ionizante , Receptores Imunológicos/agonistas , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/radioterapia , Apoptose , Proteínas Reguladoras de Apoptose/genética , Proliferação de Células , Proteína DEAD-box 58 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Proteínas de Ligação a RNA/genética , Células Tumorais Cultivadas
9.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33466757

RESUMO

Chromosomal rearrangements comprise unbalanced structural variations resulting in gain or loss of DNA copy numbers, as well as balanced events including translocation and inversion that are copy number neutral, both of which contribute to phenotypic evolution in organisms. The exquisite genetic assay and gene editing tools available for the model organism Saccharomyces cerevisiae facilitate deep exploration of the mechanisms underlying chromosomal rearrangements. We discuss here the pathways and influential factors of chromosomal rearrangements in S. cerevisiae. Several methods have been developed to generate on-demand chromosomal rearrangements and map the breakpoints of rearrangement events. Finally, we highlight the contributions of chromosomal rearrangements to drive phenotypic evolution in various S. cerevisiae strains. Given the evolutionary conservation of DNA replication and recombination in organisms, the knowledge gathered in the small genome of yeast can be extended to the genomes of higher eukaryotes.


Assuntos
Inversão Cromossômica/genética , Cromossomos Fúngicos/genética , Rearranjo Gênico/genética , Saccharomyces cerevisiae/genética , Translocação Genética/genética , Antibióticos Antineoplásicos , Bleomicina/farmacologia , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Rearranjo Gênico/efeitos dos fármacos , Rearranjo Gênico/efeitos da radiação , Modelos Genéticos , Radiação Ionizante
10.
Environ Health Prev Med ; 26(1): 14, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33494698

RESUMO

BACKGROUND: Numerous studies have concentrated on high-dose radiation exposed accidentally or through therapy, and few involve low-dose occupational exposure, to investigate the correlation between low-dose ionizing radiation and changing hematological parameters among medical workers. METHODS: Using a prospective cohort study design, we collected health examination reports and personal dose monitoring data from medical workers and used Poisson regression and restricted cubic spline models to assess the correlation between changing hematological parameters and cumulative radiation dose and determine the dose-response relationship. RESULTS: We observed that changing platelet of 1265 medical workers followed up was statistically different among the cumulative dose groups (P = 0.010). Although the linear trend tested was not statistically significant (Ptrend = 0.258), the non-linear trend tested was statistically significant (Pnon-linear = 0.007). Overall, there was a correlation between changing platelets and cumulative radiation dose (a change of ßa 0.008 × 109/L during biennially after adjusting for gender, age at baseline, service at baseline, occupation, medical level, and smoking habits; 95% confidence interval [CI] = 0.003,0.014 × 109/L). Moreover, we also found positive first and then negative dose-response relationships between cumulative radiation dose and changing platelets by restricted cubic spline models, while there were negative patterns of the baseline service not less than 10 years (- 0.015 × 109/L, 95% CI = - 0.024, - 0.007 × 109/L) and radiation nurses(- 0.033 × 109/L, 95% CI = - 0.049, - 0.016 × 109/L). CONCLUSION: We concluded that although the exposure dose was below the limit, medical workers exposed to low-dose ionizing radiation for a short period of time might have increased first and then decreased platelets, and there was a dose-response relationship between the cumulative radiation dose and platelets changing.


Assuntos
Plaquetas/efeitos da radiação , Pessoal de Saúde , Exposição Ocupacional/efeitos adversos , Doses de Radiação , Exposição à Radiação/efeitos adversos , Radiação Ionizante , Adulto , Idoso , Feminino , Pessoal de Saúde/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
11.
Anticancer Res ; 41(1): 55-70, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33419799

RESUMO

BACKGROUND/AIM: Our understanding of cancer risk from neutron exposure is limited. We aimed to reveal the characteristics of mammary carcinomas induced by neutrons. MATERIALS AND METHODS: Mammary carcinomas obtained from female Sprague-Dawley rats irradiated at 7 weeks of age with 0.97 Gy neutrons or 4 Gy γ-rays and from non-irradiated rats were classified into luminal and non-luminal subtypes by immunohistochemistry. Their mutational landscapes were determined by whole-exome sequencing. RESULTS: Neutrons significantly raised the incidence of luminal mammary carcinomas over the non-luminal subtype. Somatic mutations were identified in cancer genes involved in several signalling pathways, including Keap1/Nrf2, Pi3k/Akt and Wnt/ß-catenin. Focal copy-number losses involving cancer genes were observed mainly in carcinomas from the irradiated rats. CONCLUSION: Neutrons increase the incidence of luminal mammary carcinomas, probably through gene mutations similar to those found in human breast cancers, and focal copy-number losses including cancer genes that are characteristics of radiation-induced mammary carcinomas.


Assuntos
Variações do Número de Cópias de DNA/efeitos da radiação , Exoma , Neoplasias Mamárias Experimentais/genética , Mutação/efeitos da radiação , Radiação Ionizante , Animais , Biópsia , Biologia Computacional/métodos , Metilação de DNA , Análise Mutacional de DNA , Feminino , Humanos , Mutação INDEL , Imuno-Histoquímica , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/radioterapia , Neoplasias Induzidas por Radiação/genética , Neoplasias Induzidas por Radiação/patologia , Ratos , Sequenciamento Completo do Exoma
12.
Biochim Biophys Acta Bioenerg ; 1862(1): 148325, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065098

RESUMO

Ionizing radiation (IR) induced mitochondrial dysfunction is associated with enhanced radiation stimulated metabolic oxidative stress that interacts randomly with intracellular bio-macromolecules causing lethal cellular injury and cell death. Since mild mitochondrial uncoupling emerged as a valuable therapeutic approach by regulating oxidative stress in most prevalent human diseases including ageing, ischemic reperfusion injury, and neurodegeneration with comparable features of IR inflicted mitochondrial damage. Therefore, we explored whether mitochondrial uncoupling could also protect from IR induced cytotoxic insult. Our results showed that DNP, BHT, FCCP, and BAM15 are safe to cells at different concentrations range depending on their respective mitochondrial uncoupling potential. Pre-incubation of murine fibroblast (NIH/3T3) cells with the safe concentration of these uncouplers followed by gamma (γ)-radiation showed significant cell growth recovery, reduced ROS generation, and apoptosis, compared to IR treatment alone. We observed that DNP pre-treatment increased the surviving fraction of IR exposed HEK-293, Raw 264.7 and NIH/3T3 cells. Additionally, DNP pre-treatment followed by IR leads to reduced total and mitochondrial oxidative stress (mos), regulated calcium (Ca2+) homeostasis, and mitochondrial bioenergetics in NIH/3T3 cells. It also significantly reduced macromolecular oxidation, correlated with the regulated ROS generation and antioxidant defence system. Moreover, DNP facilitated DNA repair kinetics evidenced by reducing the number of γ-H2AX foci formation and fragmented nuclei with time. DNP pre-incubation restrained the radiation induced pro-apoptotic factors and inhibits apoptosis. Our findings raise the possibility that mild mitochondrial uncoupling with DNP could be a potential therapeutic approach for radiation induced cytotoxic insult associated with an altered mitochondrial function.


Assuntos
Mitocôndrias/metabolismo , Estresse Oxidativo , Radiação Ionizante , Espécies Reativas de Oxigênio/metabolismo , Desacopladores/farmacologia , Animais , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Células RAW 264.7
13.
Mol Med Rep ; 23(1): 1, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33215223

RESUMO

The current study investigated whether hyperoxia may reverse hypoxia­induced radioresistance (RR) in cervical cancer. Human HeLa cells exposed to hypoxic, normoxic or hyperoxic conditions were irradiated using X­rays. Cell proliferation and apoptosis were analyzed using MTT assays and flow cytometry. The expression levels of hypoxia­inducible factor­1α (HIF­1α), VEGF165, VEGFRs, Akt and ERK were measured via western blotting and/or ELISA. The results demonstrated that hypoxia stimulated HIF­1α and VEGF expression, and induced RR in HeLa cells. The administration of recombinant VEGF or the forced expression of VEGF promoted RR, whereas inactivating HIF­1α or blocking the VEGF­VEGFR interaction abrogated hypoxia­induced RR. Notably, hyperoxia decreased the level of hypoxia­stimulated HIF­1α and VEGF, and enhanced radiosensitivity in hypoxic HeLa cells. The results demonstrated that hyperoxia suppressed the hypoxia­activated Akt and ERK signaling pathways in HeLa cells. Therefore, a high O2 concentration may be considered as a radiotherapeutic sensitizer for hypoxic HeLa cells.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Oxigênio/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Apoptose , Hipóxia Celular/efeitos da radiação , Proliferação de Células , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HeLa , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tolerância a Radiação , Radiação Ionizante , Radiossensibilizantes/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Methods Mol Biol ; 2183: 331-356, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32959252

RESUMO

Vaccination was developed by Edward Jenner in 1796. Since then, vaccination and vaccine development research has been a hotspot of research in the scientific community. Various ways of vaccine development are successfully employed in mass production of vaccines. One of the most successful ways to generate vaccines is the method of virulence attenuation in pathogens. The attenuated strains of viruses, bacteria, and parasites are used as vaccines which elicit robust immune response and confers protection against virulent pathogens. This chapter brings together the most common and efficient ways of generating live attenuated vaccine strains in viruses, bacteria, and parasites.


Assuntos
Vacinas Atenuadas/imunologia , Vacinologia/métodos , Animais , Vacinas Bacterianas , Linhagem Celular , Uso do Códon , Feminino , Raios gama , Inativação Gênica , Humanos , Imunização , Imunogenicidade da Vacina , Vírus da Influenza A , Camundongos , MicroRNAs/genética , Modelos Animais , Mutagênese , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Vacinas Protozoárias/genética , Vacinas Protozoárias/imunologia , Radiação Ionizante , Vacinas Atenuadas/genética , Virulência/imunologia
15.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33374960

RESUMO

To increase the efficiency of therapy via enhancing its selectivity, the usage of gold nanorods (GNR) as a factor sensitizing cancer cells to radiation was proposed. Due to gold nanoparticles' characteristics, the smaller doses of radiation would be sufficient in the treatment, protecting the healthy tissue around the tumor. The aim of this study was to investigate the effect of gold nanorods on cancer and normal prostate cells and the role of nanorods in the cell response to ionizing radiation. The effect was evaluated by measuring the toxicity, cell cycle, cell granularity, reactive oxygen species (ROS) level, and survival fractions. Nanorods showed a strong toxicity dependent on the concentration and incubation time toward all used cell lines. A slight effect of nanorods on the cycle distribution was observed. The results demonstrated that the administration of nanorods at higher concentrations resulted in an increased level of generated radicals. The results of cellular proliferation after irradiation are ambiguous; however, there are noticeable differences after the application of nanorods before irradiation. The obtained results lead to the conclusion that nanorods affect the physiology of both normal and cancer cells. Nanorods might become a potential tool used to increase the effectiveness of radiation treatment.


Assuntos
Ouro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Radiação Ionizante , Radiossensibilizantes/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Ouro/química , Humanos , Masculino , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Microscopia Eletrônica de Transmissão , Nanotubos/química , Nanotubos/ultraestrutura , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Radiossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
16.
Cell Death Dis ; 11(12): 1068, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318475

RESUMO

Esophageal squamous cell carcinoma (ESCC), the most frequent esophageal cancer (EC) subtype, entails dismal prognosis. Hypoxia, a common feature of advanced ESCC, is involved in resistance to radiotherapy (RT). RT response in hypoxia might be modulated through epigenetic mechanisms, constituting novel targets to improve patient outcome. Post-translational methylation in histone can be partially modulated by histone lysine demethylases (KDMs), which specifically removes methyl groups in certain lysine residues. KDMs deregulation was associated with tumor aggressiveness and therapy failure. Thus, we sought to unveil the role of Jumonji C domain histone lysine demethylases (JmjC-KDMs) in ESCC radioresistance acquisition. The effectiveness of RT upon ESCC cells under hypoxic conditions was assessed by colony formation assay. KDM3A/KDM6B expression, and respective H3K9me2 and H3K27me3 target marks, were evaluated by RT-qPCR, Western blot, and immunofluorescence. Effect of JmjC-KDM inhibitor IOX1, as well as KDM3A knockdown, in in vitro functional cell behavior and RT response was assessed in ESCC under hypoxic conditions. In vivo effect of combined IOX1 and ionizing radiation treatment was evaluated in ESCC cells using CAM assay. KDM3A, KDM6B, HIF-1α, and CAIX immunoexpression was assessed in primary ESCC and normal esophagus. Herein, we found that hypoxia promoted ESCC radioresistance through increased KDM3A/KDM6B expression, enhancing cell survival and migration and decreasing DNA damage and apoptosis, in vitro. Exposure to IOX1 reverted these features, increasing ESCC radiosensitivity and decreasing ESCC microtumors size, in vivo. KDM3A was upregulated in ESCC tissues compared to the normal esophagus, associating and colocalizing with hypoxic markers (HIF-1α and CAIX). Therefore, KDM3A upregulation in ESCC cell lines and primary tumors associated with hypoxia, playing a critical role in EC aggressiveness and radioresistance. KDM3A targeting, concomitant with conventional RT, constitutes a promising strategy to improve ESCC patients' survival.


Assuntos
Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Tolerância a Radiação , Hipóxia Tumoral , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Hidroxiquinolinas/farmacologia , Histona Desmetilases com o Domínio Jumonji/genética , Tolerância a Radiação/efeitos dos fármacos , Radiação Ionizante , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/genética , Hipóxia Tumoral/efeitos da radiação
17.
Int J Mol Sci ; 21(24)2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33327380

RESUMO

Laser-driven accelerators allow to generate ultrashort (from femto- to picoseconds) high peak dose-rate (up to tens of GGy/s) accelerated particle beams. However, the radiobiological effects of ultrashort pulsed irradiation are still poorly studied. The aim of this work was to compare the formation and elimination of γH2AX and 53BP1 foci (well known markers for DNA double-strand breaks (DSBs)) in Hela cells exposed to ultrashort pulsed electron beams generated by Advanced Research Electron Accelerator Laboratory (AREAL) accelerator (electron energy 3.6 MeV, pulse duration 450 fs, pulse repetition rates 2 or 20 Hz) and quasi-continuous radiation generated by Varian accelerator (electron energy 4 MeV) at doses of 250-1000 mGy. Additionally, a study on the dose-response relationships of changes in the number of residual γH2AX foci in HeLa and A549 cells 24 h after irradiation at doses of 500-10,000 mGy were performed. We found no statistically significant differences in γH2AX and 53BP1 foci yields at 1 h after exposure to 2 Hz ultrashort pulse vs. quasi-continuous radiations. In contrast, 20 Hz ultrashort pulse irradiation resulted in 1.27-fold higher foci yields as compared to the quasi-continuous one. After 24 h of pulse irradiation at doses of 500-10,000 mGy the number of residual γH2AX foci in Hela and A549 cells was 1.7-2.9 times higher compared to that of quasi-continuous irradiation. Overall, the obtained results suggest the slower repair rate for DSBs induced by ultrashort pulse irradiation in comparison to DSBs induced by quasi-continuous irradiation.


Assuntos
Quebras de DNA de Cadeia Dupla/efeitos da radiação , Lasers , Radiação Ionizante , Células A549 , Reparo do DNA/efeitos da radiação , Células HeLa , Histonas/genética , Histonas/metabolismo , Humanos , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
18.
Adv Gerontol ; 33(4): 646-656, 2020.
Artigo em Russo | MEDLINE | ID: mdl-33342093

RESUMO

Radiation-protective and anti-aging properties are often combined. Combination of this properties is linked to the common mechanisms of action such as direct and indirect antioxidant activities, inhibition of free radicals formation, increase resistance to stress impacts at the cellular level, acceleration of DNA reparation, prevention of chronic diseases linked to abnormalities in regeneration processes, activation of immune inflammatory processes and carcinogenesis. Regulation of cell cycle and apoptosis can often be considered as an implementing driver of radiation-protective and anti-aging activities. On the one hand, against the background of stopping the cell cycle and blockade of apoptosis increases the time required to repair the defects of a DNA. Antiapoptotic effects enhances survival chances at the early stage after irradiation in a particular range of doses. On the other hand, activation of apoptosis of altered cells can be seen as one of the mechanisms to delay aging processes and prevention of isolated effects of exposure to ionizing radiation. Formation of radiation-induced and age-related alterations are characterized by multiple factors and a variety of manifestations. Nevertheless, similarity of individual links of the pathogenesis of disease related to radiation exposure and aging of the body is striking. It could be stated that radiation-protective property defines an increase in life expectancy by short-term exposure in sub-lethal and lethal doses. However anti-aging activities prevent the development of remote effects of ionizing radiation by prolonged low doses or fractionated exposure to radiation.


Assuntos
Protetores contra Radiação , Apoptose , Dano ao DNA , Relação Dose-Resposta à Radiação , Radiação Ionizante , Protetores contra Radiação/farmacologia
19.
Av. odontoestomatol ; 36(3): 131-142, sept.-dic. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-197412

RESUMO

INTRODUCCIÓN: Los exámenes radiográficos odontológicos usan radiaciones ionizantes, las que pueden producir efectos adversos en la salud de pacientes y trabajadores ocupacionalmente expuestos a radiaciones. La protección radiológica busca que la justificación de la exposición a radiación ionizante sea adecuada, y produzca al paciente mayor beneficio que riesgo. El objetivo del presente artículo es revisar los efectos adversos de las radiaciones ionizantes en el ser humano, analizar el principio de justificación y entregar recomendaciones para su aplicación en la práctica diaria odontológica, presentando guías clínicas actuales. REVISIÓN: Para cumplir con el principio de justificación, la elección de cada examen radiográfico debe realizarse responsablemente, basándose en las necesidades individuales de cada paciente. Este proceso debe realizarse conjuntamente entre clínico y radiólogo maxilofacial. A pesar de que existen numerosas guías para distintas especialidades odontológicas, desarrolladas por instituciones de diversas partes del mundo, son pocas las guías basadas en evidencia. Las guías aportan recomendaciones, con distintos niveles de evidencia, para el uso de exámenes radiográficos, permitiendo al clínico seleccionar el examen adecuado para cada paciente, contribuyendo a la disminución de exposiciones innecesarias. CONCLUSIONES: La comunicación entre clínico y radiólogo maxilofacial es fundamental para lograr el proceso de justificación, y por lo tanto, una reducción en las dosis de radiación a los pacientes. Además, es necesario el uso de guías clínicas para correcta selección del examen radiográfico. Se requiere más investigación que justifique el uso de nuevas tecnologías imagenológicas en indicaciones específicas y permitan elaborar guías clínicas basadas en evidencia


INTRODUCTION: Dental radiographic examinations use ionizing radiation, which can have adverse health effects in patients and workers occupationally exposed to radiation. Radiological protection seeks to ensure that justification for exposure to ionizing radiation is adequate, so that the patient has a greater benefit than risk. The aim of this article is to review the adverse effects of radiation on humans, to analyze the principle of justification and to provide recommendations for its application in daily dental practice, presenting current clinical guidelines. REVIEW: In order to comply with the principle of justification, the choice of each radiographic examination must be made in a responsible manner, based on the individual needs of each patient. This process should be performed jointly between the clinician and the maxillofacial radiologist. Although there are numerous guidelines for different dental specialties, developed by institutions from different parts of the world, few of them are evidence-based guidelines. Guidelines provide recommendations, with different levels of evidence, for the use of radiographic examination, allowing the clinician to select the appropriate exam for each patient, contributing to the reduction of unnecessary exposures. CONCLUSIONS: Communication between clinician and maxillofacial radiologist is essential to achieve the justification process, and therefore a reduction in radiation doses to patients. In addition, the use of clinical guidelines is necessary for a correct choice of the radiographic examination. More research is needed to justify the use of new imaging technologies in specific indications, to develop clinical evidence-based guidelines


Assuntos
Humanos , Radiação Ionizante , Raios X/efeitos adversos , Doses de Radiação , Proteção Radiológica/métodos , Tomografia Computadorizada de Feixe Cônico/instrumentação , Processos Estocásticos
20.
ACS Appl Mater Interfaces ; 12(51): 56874-56885, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33326207

RESUMO

Radiotherapy is the main treatment for cancer patients. A major concern in radiotherapy is the radiation resistance of some tumors, such as human nonsmall cell lung cancer. However, the radiation dose delivered to the tumors is often limited by the possibility of collateral damage to surrounding healthy tissues. A new and efficient gadolinium-based nanoparticle, AGuIX, has recently been developed for magnetic resonance imaging-guided radiotherapy and has been proven to act as an efficient radiosensitizer. The amplified radiation effects of AGuIX nanoparticles appear to be due to the emission of low-energy photoelectrons and Auger electron interactions. We demonstrated that AGuIX nanoparticles exacerbated radiation-induced DNA double-strand break damage and reduced DNA repair in the H1299 nonsmall cell lung cancer cell line. Furthermore, we observed a significant improvement in tumor cell damage and growth suppression, under radiation therapy, with the AGuIX nanoparticles in a H1299 mouse xenograft model. This study paves the way for research into the radiosensitization mechanism of AGuIX nanoparticles and provides a scientific basis for the use of AGuIX nanoparticles as radiosensitizing drugs.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas Metálicas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Gadolínio/química , Gadolínio/efeitos da radiação , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Nanopartículas Metálicas/química , Nanopartículas Metálicas/efeitos da radiação , Camundongos Nus , Radiação Ionizante , Radiossensibilizantes/química , Radiossensibilizantes/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
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